Triple-negative breast cancers (TNBC) exhibit aggressive tumor biology and carry a poor prognosis, particularly in premenopausal African American (AA) women who carry a disproportionate burden of breast cancer mortality. The precursor lesion for TNBC is poorly characterized and the pathophysiology of TNBC is not well understood so therapies often fail to achieve complete pathological response and the disease is frequently non-curative. This proposal aims to clarify the molecular pathology of TNBC so that biomarkers for early diagnosis, prevention strategies and curative therapies can be developed. In our high-risk, multi-institutional cohort, with a high percent of AA women, we found that during breast cancer initiation, pStat3 is high as is ECM stiffness and integrin/YAP mechanosignaling, and miRNAs implicated in tumor progression/aggression. TNBCs had the highest inflammation, pStat3 and miR-18a, the stiffest ECM and the lowest miR-203. Mouse studies indicated preventing inflammation decreases fibrosis and that reducing ECM stiffening lower pStat3 and inflammation and EMT and metastasis. Driving mammary mechanosignaling induced miR-18a and EMT and enhanced tumor aggression/metastasis. This suggests that an activated Stat3/tissue tension feedback loop, linked to tissue inflammation, promotes TNBC by engaging mechanosignaling pathways that alter miRs and induce an EMT and tumor aggression. While some breast cancers arise from focal lesions, TNBCs often appear to arise diffusely. We predict that in women at high-risk for TNBC (familial association, BRCA1 mutation) there is a dynamic and reciprocal relationship between the at risk epithelium and tissue tension that activates mechano-signaling pathways and induces Stat3/miRNA to 1) initiate TNBC, 3) induce an EMT and/or enhance tumor aggression, that 3) can be used to idenify precancerous lesions that have a high likelihood of progression to TNBC, and 4) could be used to monitor efficacy of prevention strategies and identify targets to improve TNBC treatment. We will use preclinical models to test: 1) if there is a reciprocal relationship between inflammation, pStat3 and tissue tension that promotes TNBC progression/aggression and 2) if this is mediated through miRs and EMT. We will examine a clinical cohort of high risk women who rapidly develop TNBCs to 3) test the prevalence of this signaling circuit in biopsies from women with TNBC and determine whether these biomarkers can identify precancerous lesions that have a high likelihood of progression to TNBC. Significance: Our studies could transform concepts of breast cancer by demonstrating that tissue tension could molecularly-prime tissue to malignancy. Markers that identify preneoplastic changes in TNBC, that could be used to monitor efficacy of risk reduction strategies, would have a transformative impact on TNBC mortality rates and particularly AA women.